This proposal seeks a period of supervised scientific training to enable Karin Borgmann-Winter, M.D. to develop into an independent physician-scientist. Background: Early intervention is critically important for young individuals at high risk for the development of schizophrenia; yet the effects of antipsychotics on the developing brain are largely unknown. Pre-clinical studies suggested that different antipsychotics may impact on neurotrophic or neurodevelopmental effects in the brain. These studies, however, were conducted in animal brains or in vitro cell lines, but never in neural cells derived from patients. Research Project: This study will examine the potential neurodevelopmental/neurotrophic effects of antipsychotics in young subjects with psychoses. We will employ the olfactory system as a window in which to examine the molecular and cell biological processes of neuronal development in correlation with clinical olfactory measures and symptom progression. We will examine these factors in neurons from the olfactory biopsy tissues of psychotic individuals before and after antipsychotic treatment. We will develop in vitro cultures of olfactory receptor neurons derived from biopsy tissues from young individuals with psychoses and examine the relationships between different antipsychotics, their neurotransmitter binding profiles and BDNF- TrkB signaling as a possible mechanism for the effects of antipsychotics on neurodevelopment. Environment: The primary training sites are the Cellular and Molecular Neuropathology Program, the Hahn Laboratory of the Center for Neurobiology and Behavior and the Schizophrenia Research Center at the University of Pennsylvania. Multi-disciplinary mentoring led by and Raquel E. Gur, M.D., PhD, Steven Arnold, M.D. and Chang-Gyu Hahn, M.D. Ph.D. will facilitate bi-directional translation of methodological approaches in basic science and clinical observations in young individuals with psychoses. Research Career Development: Mentorship and formal coursework will address the candidate's career development needs to: 1) Acquire additional skills needed for the design and implementation of more complex cellular and molecular biological laboratory methods. 2) Obtain training in the administration of psychophysical olfactory tests and the interpretation of olfactory data. 3) Develop additional skills in the assessment and recruitment of adolescents at high risk for schizophrenia and in early stages of psychosis. 4) Publish research findings and submit an RO1. Relevance: This proposal will examine the potential neurotoxic or neurodevelopmental effects of antipsychotics on the developing neural tissues. Such information will be crucial for determining the effects of early intervention on the developing brains of young individuals.